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Publication Shows Gene Programming Is Coming Soon

Dr. Krawetz published the cover article in a recent issue of the journal Molecular Human Reproduction.

A research paper, which was selected as the cover article in the October 2001 issue of Molecular Human Reproduction, may represent a giant leap forward in understanding gene function, as well as a step toward the holy grail of genome reprogramming.

Overall, the paper tackles gene potentiation, or how gene expression is switched on and off, according to Stephen Krawetz, Charlotte B. Failing Professor of the WSU obstetrics and gynecology department and the university’s Center for Molecular Medicine Genetics (CMMG) and Institute for Scientific Computing. “This paper shows what we believe to be one of the key elements modulating the whole potentiative mechanism, which is the opening and closing of the chromatin domain.”

The paper particularly focuses on one multigenic chromosomal locus in the sperm genome. Dr. Krawetz and the other paper authors, including Henry Heng of the CMMG, and Carl Schmidt of the University of California-Davis, investigated the mechanisms that essentially unlock the DNA in that locus and allow it be expressed to make the various protein components that package the DNA in sperm cells. They believe the mechanisms in question are controlled by the nuclear matrix attachment regions, or MARS. “MARS are absolutely critical to expressing the whole genome,” Dr. Krawetz said, adding that they now are beginning to see how they work.

The paper provides evidence against the commonly held belief that methylation status — the addition or deletion of a methyl group (-CH3) — controls how MARS are used in both gene expression and gene silencing.

“This paper is actually the first demonstration of real, defined sites of attachment of a single-copy gene in human sperm in the nuclear matrix,” he explained. “Interestingly, throughout the whole locus that we are studying, the mechanism of regulation is independent of this methylation process. This suggests that in some cases methylation may be necessary. It is only one small component that regulates our genome but is not ubiquitously utilized.”

Now they hope to use transgenic mice to test their hypothesis that these elements are involved in the opening mechanism. He expects to have results from that work next year.

If the work goes as planned, he acknowledged that it could have substantial implications. “In terms of gene therapeutics, these elements would actually allow us to modulate gene expression on a global level. If they are tissue-specific — and we suspect they are —they would only be activated in that tissue.” That would allow systemic delivery of the gene therapeutics but only activation in the target tissue.

“The other aspect of this work that is really wonderful, is that we believe it is involved in the mechanism of genome reprogramming. If you can actually identify how to activate these elements during cell division, then you can, in effect, reprogram the genome. That means we could take an adult cell and make it differentiate into something else,” Dr. Krawetz said.

While the potential applications may seem futuristic, Dr. Krawetz sees the light at the end of the tunnel. “We're getting there,” he said. “I'm hoping we're as close as I think we are.”

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